Episodic memory is defined as detail-rich and flexibly accessible memory for individual events or episodes. A key component of episodic memory is memory for the temporal order of items within an episode. While it is clear that the structures of the medial temporal lobe (MTL) and the prefrontal cortex (PFC) both contribute to memory for temporally ordered information, the nature of that contribution and the interactions between these key brain areas during temporal order memory remains to be elucidated. Also unresolved is the relative contribution of these areas to working memory versus long-term memory tasks for temporally ordered information. The proposed experiments are based on the underlying hypothesis that the MTL and PFC contribute in complementary but differentiable ways to the performance of both working memory and long- term memory tasks for temporal order memory. To test these hypotheses, we will conduct a series of hypothesis driven experiments designed to define the specific contributions and interactions of structures in the MTL and PFC during temporal order tasks requiring either working memory or long-term memory retrieval. In Specific Aim 1, we will record activity in the MTL and PFC both individually and simultaneously as animals perform a working memory temporal order memory task with objects. In Specific Aim 2, we will record simultaneously across both areas as animals perform a task requiring long-term memory for color-cue - temporal order associations. For both Aims, cross correlation analyses as well as LFP and spike-field coherence analyses will allow us to evaluate the timing and the nature of the interactions between these areas. Specifically, we predict that a major role of the MTL, mainly through the activity of the hippocampus, is to provide strong signals for particular trial events and trial timing during both the WM and the LTM versions of the temporal order task. In addition, we predict that the surrounding entorhinal and perirhinal cortex are engaged in mnemonic encoding of object and object-temporal order conjunctions for the working memory task and the perirhinal cortex is critical for the retrieval of the long-term memory for associations between color-cues and temporal order. In contrast, we hypothesize that the PFC is primarily involved in cognitive control processes including a prominent role in maintenance of temporal order information during the working memory delay period, though we may see trial timing-related activity in the PFC as well. Understanding the specific contributions and functional interactions of the MTL and PFC in temporal order memory will not only provide new insight into the fundamental cognitive function of episodic memory, but also has important implications for the development of treatments for a wide variety of disease states that affect episodic memory including Alzheimer's disease, schizophrenia, and the memory impairments present in aging. PUBLIC HEALTH RELEVANCE: Alzheimer's disease, schizophrenia, developmental disorders and aging all involve impairments in learning and memory associated with damage to the medial temporal lobe and/or the prefrontal cortex. Here we propose to use neurophysiological recording techniques to characterize the individual contributions and interactions between the structures of the medial temporal lobe and the prefrontal cortex during various tasks of temporal order memory. This information will serve as an important foundation for the development of treatments for disorders of memory that affect the medial temporal lobe, the prefrontal cortex and their interactions.